This grant application has been developed to test the hypothesis that insulin resistance and hyperglycemic trends parallel plasma cortisol levels in major depressive disorder (MDD). We will also test the more focused hypothesis that treatment of depressive symptoms ameliorates state of insulin resistance. We will approach these hypotheses by studying depressed Mexican-American women from a rigorously characterized cohort of patients who have been recruited into our NIGMS-funded project in pharmacogenomics of antidepressant treatment response (GM61394). This application builds on the enormous resource provided by that prospective study, which provides the opportunity to recruit and treat these individuals. That project is a carefully designed, prospective clinical phase IIA randomized longitudinal study, using two pharmacological agents (desipramine and fluoxetine) with demonstrated efficacy in the treatment of MDD in the Mexican-American population. Clinical status is assessed with clinical interview and ratings such as the Hamilton Ratings Scale for Depression, Beck Depression Inventory, and Hamilton Anxiety Rating Scale. These instruments have been extensively validated in Spanish. That project is a treatment study with single- and double-masking, with random assignment of treatment, and with outcomes assessed with clinical measures. All subjects will undergo comprehensive intake assessments, and will then have follow-up assessments. Treatment will be provided according to our approved protocol. We propose to conduct detailed endocrine, nutritional, and metabolic studies in normal-weight Mexican-American women, who are otherwise medically healthy and who will be extensively characterized for our pharmacogenomic study. This proposal will permit the ascertainment of degree of insulin resistance in MDD through the assessment of endocrine (HPA axis and leptin measurements), nutritional, body composition, and metabolic function (insulin sensitivity will be assessed by oral glucose tolerance test, glucose clamp and arginine stimulation test) before and after treatment. Treatment outcome data will be correlated with endocrine and metabolic endpoints. Several lines of evidence suggest diabetes mellitus is often associated with depression and that depression increases the risk of developing diabetes. This work will address this important area by the study of an population group who is markedly under represented in patient-oriented investigation.